20.500.12556/RUL-185196 Fluorinated aminopiperidones as non-glutarimide thalidomide analogs stereodivergent synthesis and validation The glutarimide fragment is a key pharmacophore in cereblon-binding immunomodulatory drugs and proteolysis-targeting chimeras, yet exploration of non-glutarimide scaffolds remains limited. Here, we report the design, synthesis, and evaluation of fluorinated aminopiperidones as three-dimensional, non-glutarimide thalidomide analogs. By replacing a single glutarimide carbonyl with a stereogenic C$^*$–CF$_{3}$ unit, we accessed a previously underexplored chemical space encompassing all regio- and diastereomeric variants of 3- and 5-phthalimido-6-trifluoromethyl-2-piperidones. Stereocontrolled synthetic routes enabled reliable control over relative configurations, and two-dimensional NMR provided unambiguous structural assignment. Experimental profiling of CF$_{3}$-piperidones relative to glutarimides revealed improved aqueous solubility despite increased logD and enhanced membrane interaction characteristics, without substantial changes in plasma protein binding, consistent with sp$^3$ enrichment and escape-from-flatland principles. To assess whether cereblon recognition is retained after carbonyl-to-C$^*$–CF$_{3}$ replacement, the compounds were evaluated by microscale thermophoresis. No measurable cereblon binding was detected for the fluorinated aminopiperidones. Docking studies, performed to rationalize this lack of affinity, suggested disruption of key cereblon–ligand interactions and unfavorable binding poses following carbonyl-to-C$^*$–CF$_{3}$ substitution. Several CF$_{3}$-piperidones, particularly tetrafluorophthalimide derivatives, exhibited potent anti-angiogenic activity in vitro and ex vivo, indicating a cereblon-independent mechanism. bioisosterism diastereoselectivity drug design fluorine PROTAC bioizosterizem diastereoselektivnost načrtovanje zdravil fluor PROTAC zdravila farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2026-07-28 08:22:38 2026-07-28 08:22:48 2026-07-29 04:03:38 0000-00-00 00:00:00 2026 0 0 15 str. iss. 13, art. e70360 Vol. 21 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 1860-7187 10.1002/cmdc.70360 284004099 ChemMedChem_-_2026_-_Adamlje_-_Fluorinated.pdf ChemMedChem_-_2026_-_Adamlje_-_Fluorinated.pdf 1 D31E5660302CF097A57FADF625C2F20C fe5f7c99ac9056fff92d289db213e05e58059aca5a6b1ec75e0e3a294ad5edf2 c28b66b0-8a4d-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=243487 https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.70360 1 7e9e9973-8a4c-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=243486 Fakulteta za farmacijo 0 0 0